Asthma is the most common chronic disease in industrialized nations, affecting >10 million people in the U.S. alone. Familial aggregation and concordance rates in monozygotic twins have suggested a genetic component to asthma. We have been conducting studies on the genetics of asthma and atopy in the Hutterites, a founder population of European origins that practices a communal lifestyle. A genome-wide screen with 564 markers (average spacing 6 cM) was completed in an extended pedigree of 717 Hutterites who were well characterized with respect to asthma, atopy, and related phenotypes. These individuals are descendants of only 64 ancestors who lived in the early 1700's to the early 1800's. Evidence for linkage with bronchial hyperresponsiveness2 (BHR) by the likelihood ratio test extended over 30 cM on chromosome 5p, with P-values as small as 0.001. Additional evidence for linkage at this same location was evident by the transmission disequilibrium test (P=0.0061). Typing additional markers in this region identified a critical region of 2.4 cM, corresponding to 1.5 Mb of DNA, and a high risk haplotype that is over transmitted to affected individuals. In this application, we propose to characterize the 5p-linked BHR susceptibility locus in the Hutterites by positional cloning and to replicate these findings in outbred, ethnically diverse populations. We will examine single nucleotide polymorphisms (SNPs) spaced about 10 kb apart in each gene, and assess the evidence for over transmission to affected offspring with each SNP and SNP haplotypes. Associations in the Hutterites will be replicated in the outbred samples. The functional effects of associated variants will be assessed by in vitro assays as well as by genotype-phenotype studies in outbred samples that have been evaluated for asthma and atopy phenotypes. Identifying asthma or BHR susceptibility loci may identify novel pathways in asthma pathogenesis, thereby allowing for the development of new therapies and intervention strategies for these common diseases.